SB-656933, a novel CXCR2 selective antagonist, inhibits ex vivo neutrophil activation and ozone-induced airway inflammation in humans

Br J Clin Pharmacol. 2011 Aug;72(2):282-93. doi: 10.1111/j.1365-2125.2011.03968.x.


What is already known about this subject: Receptor antagonists that block the binding of chemokines such as CXCL8 (IL-8) are effective in animals models of neutrophil-mediated inflammation. It has been hypothesized that selective inhibition of neutrophil trafficking and activation may be a useful adjunct for the treatment of inflammatory airway diseases such as chronic obstructive pulmonary disease or cystic fibrosis. A CXCR1/2 receptor antagonist has shown activity in an ozone challenge model in humans.

What this study adds: SB-656933, a selective CXCR2 antagonist, is safe and well-tolerated at single doses and is shown to inhibit agonist (CXCL1)-mediated expression of the CD11b on peripheral blood neutrophils as well as ozone-induced airway neutrophilia in healthy subjects.

Aims: To determine the safety and tolerability of a novel selective CXCR2 antagonist and assess its pharmacodynamic effects using measures of neutrophil activation and function, including CD11b expression in whole blood and ozone-induced airway inflammation in healthy subjects.

Methods: Flow cytometric determination of ex vivo CXCL1-induced CD11b expression on peripheral blood neutrophils was performed following single dose oral administration of SB-656933 (dose range 2-1100 mg). A subsequent randomized study (placebo, 50 mg and 150 mg) was performed to explore the dose-response for ozone-induced airway inflammation, as measured by sputum biomarkers.

Results: Oral administration of SB-656933 resulted in significant inhibition of CXCL1-induced CD11b expression on peripheral blood neutrophils at single doses greater than or equal to 50 mg. Maximum inhibition (70%) relative to placebo was observed following administration of SB-656933 400 mg (95% CI 60%, 77%). This was sustained up to a dose of 1100 mg. Single doses of SB-656933 reduced ozone-induced airway inflammation in a dose-dependent manner. Relative to placebo, there were 55% (95% CI 20%, 75%) and 74% (95% CI 55%, 85%) fewer neutrophils in the sputum of subjects after a single dose of 50 mg or 150 mg, respectively. There was a corresponding reduction in myeloperoxidase concentrations in the sputum supernatant of 32.8% (95% CI 9.2, 50.3) and 50.5% (95% CI 33.3, 63.3). SB-656933 was safe and well-tolerated at all doses.

Conclusions: SB-656933 is a CXCR2 antagonist that demonstrates dose-dependent effects on neutrophil activation and recruitment within a well-tolerated dose range. These data suggest that SB-656933 may be an effective agent in neutrophil-predominant diseases.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Bronchitis / chemically induced
  • Bronchitis / immunology
  • Bronchitis / prevention & control*
  • CD11b Antigen / metabolism
  • Chemokine CXCL1 / antagonists & inhibitors
  • Cross-Over Studies
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Humans
  • Leukocyte Count
  • Male
  • Middle Aged
  • Neutrophil Activation / drug effects*
  • Neutrophils / immunology*
  • Ozone / adverse effects*
  • Peroxidase / metabolism
  • Phenylurea Compounds / pharmacokinetics
  • Phenylurea Compounds / pharmacology*
  • Receptors, Interleukin-8B / antagonists & inhibitors*
  • Receptors, Interleukin-8B / metabolism
  • Single-Blind Method
  • Sputum / enzymology
  • Sulfonamides / pharmacokinetics
  • Sulfonamides / pharmacology*
  • Young Adult


  • CD11b Antigen
  • CXCL1 protein, human
  • Chemokine CXCL1
  • Phenylurea Compounds
  • Receptors, Interleukin-8B
  • SB 656933
  • Sulfonamides
  • Ozone
  • Peroxidase